In process technology and medicine it is often necessary to determine the presence and possibly also the concentration of a preselected analyte rapidly and as continuously as possible. A number of probes and sensors are used for this purpose. For example, an immersion probe is known from WO 00/25107, which is immersed in an analyte containing medium—for example the interior of a bioreactor—and an analyte is detected therein. The immersion probe is separated from the medium to be analysed by a membrane that is permeable to the analyte. It has however been found disadvantageous, in particular when monitoring a bioreactor, that with this design of analysis apparatus it is no longer possible to dilute the analyte to be analysed. Accordingly, only those sensors whose maximum measurement range is greater than the highest analyte concentration to be expected can realistically be used. The sensor would otherwise always display the maximum measurement value irrespective of the actual analyte concentration. With this analysis apparatus the measurement range within which the concentration of the analyte can be determined is therefore restricted.
This is particularly disadvantageous when monitoring biotechnological and medical processes, for example in a continuous monitoring of the blood sugar level of a diabetic patient. Especially with diabetic patients, the blood sugar concentration can fluctuate wildly within a short period of time, which requires a rapid administration of insulin that is accurately matched to the respective blood sugar concentration. There is therefore a constant need, specifically in medicine and biotechnology, for rapid, sensitive and accurate analysis methods for monitoring of the preselected analytes, as well as corresponding apparatuses.
In this connection EP 0 441 179 A1 discloses a portable analysis apparatus for the continuous determination of the glucose concentration in the blood of a diabetic patient over a period of 24 to 36 hours. The analysis apparatus includes a microdialysis needle that is introduced via a venous catheter into a vein of the patient to be monitored. The microdialysis needle includes a glucose-permeable dialysis membrane, so that glucose from the patient's blood can diffuse into a space located behind the dialysis membrane. This space is constantly flushed out by a dialysis fluid, the glucose-containing dialysis fluid being passed to a sensor. The sensor is installed in a portable apparatus, which also contains a reservoir of dialysis fluid and a receptacle for spent dialysis fluid. The sensor is connected to the microdialysis needle via a very thin flexible tube with an internal diameter of 0.1 mm, in order to allow a rapid transport of glucose from the micodialysis needle to the sensor. A disadvantage of this apparatus however is that the very thin flexible tube generates a very high transport resistance and therefore pressure, which means that there is a danger that the dialysis membrane or the flexible tube will rupture. A further disadvantage is the fact that there is no possibility of carrying out a null line (base line) adjustment of the sensor during the operation of the analysis apparatus. There is therefore the danger that the measurement accuracy of the sensor will be impaired over long periods of use.
From U.S. Pat. No. 6,852,500 B1 an analysis method is known for deterring the glucose concentration in a body fluid. In this case a dialysis fluid is pumped in a pulsed manner to a sensor through a dialysis cell which on one side is in contact with the glucose-containing body fluid to a sensor, which in one pulse is glucose-free and accordingly can receive glucose from the body fluid via the dialysis membrane, and which is a further pulse contains a known glucose concentration. In this way it should be possible to measure the glucose concentration in the body fluid to be analysed at intervals of in each case 9 minutes. A disadvantage of this method is on the one hand the relatively slow cycle time of 9 minutes, and on the other hand also the complicated control of the method and the high consumption of dialysis fluid due to repeated administration of a dialysis solution of known glucose concentration.
DE 27 37 922 A1 again discloses an analysis apparatus for monitoring a blood glucose concentration. The analysis apparatus again has a dialysis membrane for separating glucose from further blood constituents. The dialysis fluid should in this connection be cycled via an enzymatic glucose sensor (glucose oxidase with oxygen electrode) through the dialysis membrane. If necessary a calibration solution can be metered in, in a pulsed manner. The disadvantage however is that due to the closed cycle of the dialysis fluid during the conventional operation of such an apparatus. A complete equilibration of the concentration of glucose in the dialysis fluid and in the blood of a monitored patient occurs, so that the sensor is again to some extent loaded with very high glucose concentrations. Accordingly the sensor must have a very wide measurement range, or must be correspondingly insensitive. Due to the high operation stress on the sensor there is also the danger that the latter will quickly become inactivated.
U.S. Pat. No. 4,245,634 discloses an analysis apparatus in the form of an artificial pancreas, in which blood diluted by infusion with heparin solution is taken from a patient through a double-bore catheter and the blood glucose concentration is measured photometrically. The disadvantage in this case is that the measurement accuracy depends on the pumping rate of the infused heparin solution. In addition there are no possibilities of performing calibrations.
US 2006/0009727 A1 discloses an analysis apparatus for the extra-corporeal determination of a blood glucose concentration. In this case circulating blood is taken from a patient through a double-bore catheter and a glucose-containing ultrafiltrate is separated via an ultrafiltration unit, the ultrafiltrate being passed to a glucose sensor. The ultrafiltrate is collected and reinfused into the patient from time to time in order to keep the volume loss of blood fluid low. For purposes of calibration a calibration fluid is fed in through a calibration sensor. Whereas in normal operation the calibration sensor is flushed with ultrafiltrate, for the calibration the flow direction is reversed, the ultrafiltrate is forced back into the ultrafiltration unit and the calibration sensor is charged with calibration fluid. The disadvantage of this arrangement is the complicated construction of the apparatus and the need to force the ultrafiltrate back into the ultrafiltration unit for purposes of calibration.